Pancreatic carcinomas are one of the most aggressive types of cancers, and patients who are diagnosed with pancreatic cancer experience a five-year survival rate of less than 4 percent with conventional chemotherapy and radiation therapy. Thus, new therapeutic strategies for the treatment of pancreatic cancer are greatly needed. Fatty acid synthase (FASN) is a 7-domain enzyme that is responsible for the de novo synthesis of free fatty acids in lipogenic tissues, and FASN expression is very low in normal cells in well-nourished individuals. FASN is overexpressed in both pre-cancerous pancreatic lesions and pancreatic adenocarcinomas, but is not expressed in normal pancreatic ductal epithelium, and this overexpression has been associated with increased resistance to chemotherapeutic intervention, increased tumor recurrence and poorer prognosis for patients with pancreatic cancer. An increase in FASN expression appears to be essential for cancer cell survival, although the mechanism by which increased FASN expression confers a survival advantage is currently unknown. Because of the differences in FASN expression levels between normal and pancreatic cancer cells, inhibiting FASN for cancer chemotherapy allows for the selective and specific targeting of pancreatic tumor cells with a high therapeutic window. Orlistat is an FDA approved drug for weight loss, and also acts as an antagonist toward the thioesterase domain of human FASN. However, orlistat is hydrolyzed by thioesterase, making it less stable and ineffective. The central hypothesis to be tested in this study is that the flexibility of the hexanoyl moiety of orlistat promotes its hydrolysis and limits its ability to target the thioesterae domain of FASN, and compounds that lack hydrolysis capacity will have greater endurance at blocking thioesterase activity. To test this hypothesis, I will accomplish three specific aims: (1)to investigate the course of events that occur after orlistat has formed a covalent bond to the FASN thioesterase domain using molecular dynamics simulations; (2) to identify potential inhibitors of FASN thioesterase; and (3) to evaluate the therapeutic potential of selected compounds.